PROJECT SUMMARY/ABSTRACT The purpose of this project is to provide scientific data to the Food and Drug Administration (FDA) Center for Tobacco Products (CTP) to support setting nicotine standards for tobacco products to reduce their addictiveness and adverse public health impact. This proposal addresses the specific RFA-OD-15-006 priority area of using animal models to study adolescent nicotine reinforcement and use behaviors, including initiation. In order to achieve the greatest net population impact, ?targeted tobacco regulatory science? is needed to take into account the variability in risk of nicotine addiction between vulnerable subpopulations.. Applying nicotine standards to the general population that are based on vulnerable subgroups will achieve the greatest net population reduction in smoking and improvement in public health. The overall aim of this project is to determine whether depression or attention deficit hyperactivity disorder (ADHD) predispose adolescents to nicotine addiction by lowering the nicotine reinforcement threshold. Adolescents with comorbid depression and Attention Deficit Hyperactivity Disorder (ADHD) have a higher incidence of smoking, start smoking at a younger age, exhibit a faster progression to daily smoking and dependence, and are less successful quitting. We hypothesize that the greater vulnerability of these subgroups is due to their greater sensitivity to nicotine reinforcement (i.e. a lower nicotine reinforcement threshold). Experimental analysis of initiation of smoking in adolescents, and control of nicotine or other drug exposure in general, is difficult or impossible to accomplish in human studies, but can be addressed with animal models. Thus, animal research is vital to the FDA CTP to obtain the most comprehensive and accurate scientific information on which to base a ruling for nicotine standards for tobacco products. Given the greater vulnerability to addiction of adolescents with the comorbidities mentioned above, specific aims of this project are to test the general hypothesis that the nicotine reinforcement threshold is lower in adolescent rat models of depression (Flinders Sensitive Line, Aim 1), and ADHD (Spontaneously Hypertensive Rat, Aim 2) compared to control strains. In each model, the threshold reinforcing nicotine dose for acquisition of nicotine self-administration (NSA) will be determined during adolescence. Elasticity of demand for nicotine (i.e. sensitivity to price) will also be conducted to assess persistence of NSA during increases in price of nicotine (i.e., difficulty reducing intake). In addition, the ability of strain and individual differences in nicotine pharmacokinetics and sex differences to modulate or predict these measures of NSA will be assessed. These data will provide insight into the relative risk of nicotine reinforcement in adolescents, and how these are modified by key comorbidities and other individual differences. This type of ?targeted tobacco regulatory science? is vital to the efforts of the FDA CTP to establish nicotine standards sufficient to prevent smoking initiation in both the general population and vulnerable subpopulations of adolescents, and thereby maximize the net population impact of a nicotine reduction policy on public health.